Effectiveness of first and second COVID‐19 mRNA vaccine monovalent booster doses during a period of circulation of Omicron variant sublineages: December 2021–July 2022

Abstract Background US recommendations for COVID‐19 vaccine boosters have expanded in terms of age groups covered and numbers of doses recommended, whereas evolution of Omicron sublineages raises questions about ongoing vaccine effectiveness. Methods We estimated effectiveness of monovalent COVID‐19 mRNA booster vaccination versus two‐dose primary series during a period of Omicron variant virus circulation in a community cohort with active illness surveillance. Hazard ratios comparing SARS‐CoV‐2 infection between booster versus primary series vaccinated individuals were estimated using Cox proportional hazards models with time‐varying booster status. Models were adjusted for age and prior SARS‐CoV‐2 infection. The effectiveness of a second booster among adults ≥50 years of age was similarly estimated. Results The analysis included 883 participants ranging in age, from 5 to >90 years. Relative effectiveness was 51% (95% CI: 34%, 64%) favoring the booster compared with primary series vaccination and did not vary by prior infection status. Relative effectiveness was 74% (95% CI: 57%, 84%) at 15 to 90 days after booster receipt, but declined to 42% (95% CI: 16%, 61%) after 91 to 180 days, and to 36% (95% CI: 3%, 58%) after 180 days. The relative effectiveness of a second booster compared to a single booster was 24% (95% CI: −40% to 61%). Conclusions An mRNA vaccine booster dose added significant protection against SARS‐CoV‐2 infection, but protection decreased over time. A second booster did not add significant protection for adults ≥50 years of age. Uptake of recommended bivalent boosters should be encouraged to increase protection against Omicron BA.4/BA.5 sublineages.


| INTRODUCTION
Clinical trials supporting emergency use authorization of COVID-19 messenger RNA (mRNA) vaccines in the United States estimated the efficacy of a two-dose series to be >90% in preventing symptomatic infection. 1,2 Post-authorization observational studies continued to estimate high vaccine effectiveness (VE) against symptomatic infection, even after the emergence of the SARS-CoV-2 Alpha and Delta variants. 3 In November 2021, a monovalent booster dose of COVID-19 vaccine targeting the original SARS-CoV-2 strain was recommended for high-risk groups, citing concerns of waning immunity, decreasing VE, and increasing Delta variant incidence throughout the United States. 4 Recommendations for a booster dose were gradually expanded to include all people aged ≥12 years in the United States as of January 5, 2022 in an effort to improve protection against the Omicron variant, which was rapidly increasing in the United States. 5 In contrast to previous SARS-CoV-2 variants of concern, the Omicron variant evaded immunity from prior infection and incidence of breakthrough infections among the vaccinated increased. 6,7 Yet, VE against severe outcomes remained high, particularly among those who received a booster dose. 8 18,19 Vaccination recommendations in the United States have also continued to evolve. On March 29, 2022, a second monovalent booster dose targeting the original SARS-CoV-2 was authorized and recommended for US adults aged ≥50 years and individuals with immunocompromising conditions. 20 Children of ages five to 11 were then authorized to receive a first booster dose on May 17, 2022. 21 During a period of circulation of Omicron variant sublineages, we estimated relative VE of mRNA booster vaccination versus two-dose primary series in an ongoing community cohort with active illness surveillance in rural central Wisconsin, USA. We also estimated the relative VE of a second booster versus a single booster in adults aged ≥50 years.

| Study population and data collection
The Prospective Assessment of COVID-19 in a Community (PACC) study is an ongoing longitudinal cohort. Participants in the overall PACC cohort include persons of any age who were randomly sampled and recruited from a defined community cohort in which nearly all residents receive care from the Marshfield Clinic Health System (MCHS). 22

| SARS-CoV-2 identification
Participants completed a weekly symptom survey and were instructed to immediately report the onset of new respiratory symptoms. During the entire study period, an anterior nasal swab was self-or parentcollected when participants reported ≥1 of the following symptoms: fever, cough, loss of smell or taste, sore throat, muscle/body aches, shortness of breath, or diarrhea. In addition, participants self-or parent-collected a specimen each week, regardless of symptoms, during the period of January 27, 2022 to July 28, 2022. Compliance with weekly swabbing was over 85%. Study specimens were tested by [Janssen]) (N = 46) or mixed mRNA products (N = 1) for their primary series were excluded. Participants were described according to age groups corresponding to those for which COVID-19 vaccine authorization, recommendations, and prioritization have been based (5-11, 12-17, 18-49, 50, and ≥65 years of age). Sparse data required collapsing some of these age groups (e.g., 5-17 and ≥50 years of age) for age stratified VE estimates.  (Table S2). Only prior SARS-CoV-2 infection was retained with age in final models as sex and chronic conditions did not change the effect estimated by ≥10%.
We hypothesized that immunocompromised state or having previous COVID-19 infection might modify VE. Therefore, we performed the following sensitivity analyses to estimate relative VE: (1) excluding the small number of participants who reported that they were in an immunocompromised state and (2)  The effectiveness of a second monovalent COVID-19 mRNA vaccine booster dose relative to receipt of a single booster dose was estimated among PACC participants ≥50 years of age who were followed from March 29, 2022 to July 28, 2022 and were eligible for a fourth dose ≥4 months post booster dose receipt. Statistical methods were similar to those for the analysis comparing single booster dose effectiveness relative to primary series.

| RESULTS
There were 883 participants included in the analysis. Participants ranged in age from 5 to >90 years (median: 55, IQR: 34-71), 61% were female, and 56% had ≥1 chronic health condition (Table 1)    outside the submitted work. All other authors report no potential conflicts.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

ETHICS APPROVAL STATEMENT
This study was reviewed and approved by the Institutional Review Board at the Marshfield Clinic Research Institute.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13104.

DISCLAIMER
The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC).